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Pourquié Lab
Olivier Pourquié, Ph.D.
Investigator
olp@stowers.org
Pourquié Lab Research Website
     The goal of my research is to gain a better understanding of the segmentation process in vertebrates. Segmentation is the embryonic process whereby the body axis forms as a series of repeated anatomical modules. In humans, the segmented aspect is particularly conspicuous at the level of the vertebral column. The segmental pattern is established during embryogenesis when somites, the precursors of muscles and vertebrae, are segregated in a periodic fashion from precursors located in the presomitic mesoderm (PSM).

     My laboratory identified a molecular oscillator, termed the segmentation clock, which ticks in somitic precursors with a rhythm paralleling that of somite formation. Our ongoing research focuses on the elucidation of the molecular mechanism underlying the clock oscillator, as well as on the precise role of the clock in the vertebrate segmentation process.

Segmentation is a major embryonic patterning process
     The segmented or metameric aspect of the body axis is a basic characteristic of many animal species ranging from invertebrates to humans, and segmentation has long been thought to be a key aspect of the basic design of animals. Conservation of the segmented body pattern among very distantly related species provided a strong argument in favor of the “unity of animal body plan” idea developed at the beginning of the 19th century. Because body segmentation is one of the most salient features of the embryo, it was used as a morphological criteria in the pioneering genetic screens performed in the fruit fly by Nusslein-Volhard and Wieschaus during the late 1970s. These screens led to the identification of the genetic cascade involved in establishing the metameric pattern of the fly embryo. Many of the genes identified through these screens (e.g., wingless or hedgehog) proved to be part of major signaling systems which are deregulated in diseases such as cancer.

Somite formation
     The vertebrate body is built on a metameric organization which consists of a repetition along the antero-posterior axis of functionally equivalent units: each comprising a vertebra, its associated muscles, peripheral nerves and blood vessels. At the functional level, segmentation is critical to ensure the movements of a rod-like structure such as the vertebral column. The segmented distribution of the vertebrae derives from the earlier metameric pattern of the embryonic somites which are epithelial spheres generated in a rhythmic fashion from the mesenchymal PSM. In contrast to the fly embryo in which segments are determined simultaneously, vertebrate segmentation is a sequential process that proceeds synchronously with the posterior extension of the embryo. After the completion of gastrulation during which the superficial tissues are internalized to form the mesoderm and the endoderm, the embryo begins to elongate at its posterior end. This elongation process leads to the sequential formation of embryonic tissues in an anterior-to-posterior sequence. This progressive mode of formation of the body results in the establishment of a gradient of maturation along the antero-posterior axis. Somite formation follows this differentiation gradient and proceeds rhythmically from head to tail in all vertebrate embryos including humans. In the mouse embryo, a new pair of somites is added immediately posterior to the last formed somite pair every 120 minutes until 65 somite pairs are formed.

The vertebrate segmentation clock
     Theoretical models of vertebrate segmentation proposed the existence of an oscillator in PSM cells that acts to generate a temporal periodicity, which then translated into the spatial periodicity of somite boundaries. Work from my laboratory reporting the existence of rhythmic waves of expression of the mRNA coding for the transcription factor c-hairy1, exhibiting a period similar to that of somitogenesis, provided the first evidence for the existence of an oscillator associated to the segmentation process.

     We and others subsequently showed that this oscillator, or “segmentation clock,” controls the rhythmic transcription of a group of genes now referred to as “cyclic genes.” The segmentation clock has been identified in fish, chicks and mice, indicating that it represents a conserved feature among vertebrates.

     One of the outputs of the oscillator is the rhythmic activation of Notch in the PSM, which could act as a periodic trigger initiating the process of somite boundary specification. Our current understanding of the clockwork of the oscillator involves a series of negative feedback loops involving Notch and Wnt signaling. Recently, we have been developing a microarray approach to identify all the cyclic genes in the mouse transcriptome. Unraveling the molecular processes underlying the segmentation clock is a major focus of my laboratory.

Fgf signaling plays a major role in segmentation
     Whereas the segmentation clock is believed to set the rhythm of somitogenesis, it does not specify the positioning of somite boundaries along the antero-posterior axis. We recently demonstrated that the mechanism controlling the spacing of the future somite boundaries in the forming PSM relies on a traveling threshold of FGF signaling. We showed that segments become genetically defined in the PSM at a permissive level of FGF signaling — called the determination front — where cells become competent to respond to a periodic signal from the segmentation clock. This system results in the segment-wide expression of genes (e.g., the transcription factors of the Mesp family) which control subsequent steps of somite formation.

     We observed that fgf8 mRNA is constantly transcribed in the precursors of the PSM in the tail bud during axis extension, and that its transcription stops in descendants of these cells when they enter the posterior PSM. The posterior growth of the vertebrate axis coupled to the progressive decay of the fgf8 mRNA in the PSM results in the formation of an mRNA gradient along the PSM. Due to the axis elongation process, which results in the constant addition of new cells expressing high levels of fgf8 mRNA selectively in the posterior PSM, the gradient is dynamic and is constantly displaced posteriorly. This mechanism ensures a tight coupling of segmentation to the axis formation.

Control of somite left-right symmetry and regional identity of somitic derivatives
     A striking feature of somites is their perfect symmetry along the left-right axis, which can be contrasted with the general asymmetry of the internal organs such as heart or liver. This symmetrical pattern results from the coordinated production of pairs of somites at the anterior extremity of the PSM. We recently showed that retinoic acid plays a critical role in this coordination process by preventing the response of future somitic cells to signals from the left-right patterning machinery. We are interested in trying to understand the mechanisms that control the left-right symmetry of somite production and of the embryo in general.

     In addition, we are also interested in the mechanisms involved in the control of the regionalization of somite derivatives. Hox genes play a major role in specifying the regional identity of vertebrae, and we are actively studying how Hox gene expression is coordinated to the segmentation process.

Human segmentation syndromes
     Congenital vertebral malformations in humans represent a major therapeutic challenge due to the intricate neural and musculoskeletal anatomy of the spine. The results of our research are expected to have a strong impact in the field of congenital spine anomalies, currently an understudied biomedical problem, and will be of utility in elucidating the etiology and eventual prevention of these disorders. This work is also expected to further our understanding of the major signaling pathways underlying segmentation and establishment of the vertebrate body plan, which include Notch, Wnt, FGF and retinoic acid pathways-all known to play important roles in a wide array of human diseases.

     This work is supported by the Stowers Institute for Medical Research and Howard Hughes Medical Institute, and by grants from the National Institutes of Health and the Muscular Dystrophy Association.

Academic Appointment: Professor, Department of Anatomy & Cell Biology, KU Medical School

Selected publications

Cornier AS, Staehling-Hampton K, Delventhal K, Saga Y, Caubet JF, Sasaki N, Ellard S, Young E, Ramirez N, Carlo SE, Torres J, Emans JB, Turnpenny PD, Pourquié O. Mutation in the MESP2 Gene Cause Spondylothoracic Dysostosis/Jarcho-Levine Syndrome. Am J Hum Genet. 2008;doi:10.1016/jajhg.2008.04.014.

Dequeant ML, Pourquié O. Segmental patterning of the vertebrate embryonic axis. Nat Rev Genet. 2008. Abstract

Gomez C, Ozb udak E, Baumann D, Lewis J, Pourquié O. Control of Segment number in vertebrate embryos. Nature. 2007.

Vilhais-Neto GC, Pourquié O. Retinoic Acid. Curr Biol. 2008;18:550-552. Abstract

Benazeraf B, Pourquié O. Developmental Biology: Cell Intercalation One Step beyond. Curr Biol. 2008;18:R119-R121. Abstract

Goldbeter A, Pourquié O. Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways. J Theor Biol. 2008.

Aulehla A, Wiegraebe W, Baubet V, Wahl MB, Deng C, Taketo M, Lewandoski M, Pourquié O. A beta-catenin gradient links the clock and wavefront systems in mouse embryo segmentation. Nat Cell Biol. 2008;10:186-193. Abstract

Wahl MB, Deng C, Lewandoski M, Pourquié O. FGF signaling acts upstream of the NOTCH and WNT signaling pathways to control segmentation clock oscillations in mouse somitogenesis. Development. 2007;134:4033-4041. Abstract

Iimura T, Pourquié O. Manipulation and Electroporation of the Avian Segmental Plate and Somites in Vitro. Methods in Avian Embryology. 2nd Edition ed; 2007.

Pourquié O. Building the spine: the vertebrate segmentation clock. Clocks and Rhythms Symposium 2007;72:445-449

Pourquié O. Editorial on segmentation focus. Dev Dyn. 2007;236:1377-1378. Abstract

Turnpenny PD, Alman B, Cornier AS, Giampietro PF, Offiah A, Tassy O, Pourquié O, Kusumi K, Dunwoodie S. Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dyn. 2007;236:1456-1474. Abstract

Goldbeter A, Gonze D, Pourquié O. Sharp developmental thresholds defined through bistability by antagonistic gradients of retinoic acid and FGF signaling. Dev Dyn. 2007;236:1495-1508. Abstract

Iimura T, Pourquié O. Hox genes in time and space during vertebrate body formation. Development, growth & differentiation. 2007;49:265-275. Abstract

Iimura T, Yang X, Weijer CJ, Pourquié O. Dual mode of paraxial mesoderm formation during chick gastrulation. Proc Natl Acad Sci U S A. 2007;104:2744-2749. Abstract

Aulehla A, Pourquié O. On periodicity and directionality of somitogenesis. Anatomy and embryology. 2006;211 Suppl 7:3-8. Abstract

Dequeant ML, Glynn E, Gaudenz K, Wahl M, Chen J, Mushegian A, Pourquié O. A complex oscillating network of signaling genes underlines the mouse segmentation clock. Science. 2006;314:1595-1598. Abstract

Iimura T, Pourquié O. Collinear activation of Hoxb genes during gastrulation is linked to mesoderm cell ingression. Nature. 2006;442:568-571. Abstract

Dale JK, Malapert P, Chal J, Vilhais-Neto G, Maroto M, Johnson T, Jayasinghe S, Trainor P, Herrmann B, Pourquié O. Oscillations of the snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev Cell. 2006;10:355-366. Abstract

Hilgers V, Pourquié O, Dubrulle J. In vivo analysis of mRNA stability using the Tet-Off system in the chicken embryo. Dev Biol. 2005;284:292-300. Abstract

Delfini MC, Dubrulle J, Malapert P, Chal J, Pourquié O. Control of the segmentation process by graded MAPK/ERK activation in the chick embryo. Proc Natl Acad Sci U S A. 2005;102:11343-11348. Abstract

Dequeant ML, Pourquié O. Chicken genome: new tools and concepts. Dev Dyn. 2005;232:883-886. Abstract

Vermot J, Pourquié O. Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos. Nature. 2005;435:215-220. Abstract

Maroto M, Dale JK, Dequeant ML, Petit AC, Pourquié O. Synchronised cycling gene oscillations in presomitic mesoderm cells require cell-cell contact. Int J Dev Biol. 2005;49:309-315. Abstract

Pourquié O. Signal transduction: a new canon. Nature. 2005;433:208-209. Abstract

Pourquié O. Segmentation and somitogeneisis in vertebrates. McGraw-Hill Yearbook of Science & Technology 2005. New York ; London: McGraw-Hill; 2004:432.

Pourquié O; and the International Chicken Genome Sequencing Consortium. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature. 2004;432:695-716. Abstract

Dubrulle J, Pourquié O. Coupling segmentation to axis formation. Development. 2004;131:5783-5793. Abstract

Weiner JA, Koo SJ, Nicolas S, Fraboulet S, Pfaff SL, Pourquié O. Sanes JR. Axon fasciculation defects and retinal dysplasias in mice lacking the immunoglobulin superfamily adhesion molecule BEN/ALCAM/SC1. Mol Cell Neurosci. 2004;27:59-69. Abstract

Pourquié O. The chick embryo: a leading model in somitogenesis studies. Mech Dev. 2004;121:1069-1079. Abstract

Dubrulle J, Pourquié O. fgf8 mRNA decay establishes a gradient that couples axial elongation to patterning in the vertebrate embryo. Nature. 2004;427:419-422. Abstract

Burt D, Pourquié O. Chicken genome--science nuggets to come soon. Science. 2003;300:1669.

Dale K, Maroto M, Dequeant ML, Malapert P, McGrew M, Pourquié O. Periodic inhibition of Notch signalling by Lunatic Fringe controls cyclic gene expression in the chick presomitic mesoderm. Nature. 2003;421:275-278. Abstract.

Dubrulle J, Pourquié O. Welcome to syndetome. A new somitic compartment. Dev Cell. 2003;4:611-612. Abstract

Pourquié O. The segmentation clock: converting embryonic time into spatial pattern. Science. 2003;301:328-330. Abstract

Pourquié O. Vertebrate somitogenesis: a novel paradigm for animal segmentation? Int J Dev Biol. 2003;47. Abstract

Pourquié O, Goldbeter A. Segmentation clock: insights from computational models. Curr Biol. 2003;13:R632-634. Abstract

Stainier DY, Pourquié O. Entrails, heart, brain, limbs, and lymphatics- a recipe for success? Dev Cell. 2003;5:193-196. Abstract

Dubrulle J, Pourquié O.  From head to tail: links between the segmentation clock and antero-posterior patterning of the embryo. Curr Opin Genet Devel. 2002;12:519-523. Abstract.

Jouve C, Iimura T, Pourquié O. Onset of the segmentation clock in the chick embryo: evidence for oscillations in the somite precursors in the primitive streak. Development. 2002;129:1107-1117. Abstract.

Pourquié O. Vertebrate segmentation : Lunatic transcriptional regulation. Curr Biol.2002;15:R699-R701. Abstract.

Dubrulle J, McGrew MJ, Pourquié O.  FGF signaling controls somite boundary position and regulates segmentation clock control of Spatiotemporal Hox gene activation. Cell. 2001;106:219-232. Abstract.

Hirsinger E, Malapert P, Dubrulle J, Delfini MC, Duprez D, Henrique D, Ish-Horowicz D, Pourquié O. Notch signalling acts in postmitotic avian myogenic cells to control MyoD activation. Development. 2001;128:107-116. Abstract.

Maroto M, Pourquié O. A Molecular Clock involved in Somitogenesis. Curr Top Devel Biol. 2001;51:221-48. Abstract.

Petit, Bihel F, Alves DaCosta C, Pourquié O, Checler F, Kraus JL. New protease inhibitors prevent gamma-secretase mediated production of Abeta40/42 without affecting Notch cleavage. Nat Cell Biol. 2001;3:507-511. Abstract.

Pourquié O, Dale K, Dubrulle J, Jouve C, Maroto M, McGrew M. A molecular clock linked to vertebrate segmentation. In: Ordahl CP, Lash JW, Sanders EJ, eds. The Origin and Fate of Somites. Amsterdam, The Netherlands:IOS press;2001:64-70.

Pourquié O, Tam PP.  A nomenclature for prospective somites and phases of cyclic gene expression in the presomitic mesoderm. Dev Cell. 2001;5:619-620. Abstract.

Pourquié O.  Developmental biology: a macho way to make muscles. Nature. 2001;409:679-80. Abstract.

Pourquié O. Vertebrate somitogenesis. Ann Rev Cell Devel Biol. 2001;17:311-50. Abstract.

Pourquié O. The vertebrate segmentation clock. J Anat. 2001;199:169-175. Abstract.

Pourquié O, Kusumi K. When body segmentation goes wrong. Clin Genet. 2001;60:409-416. Abstract.

Dale K, Pourquié O. A Clock-work somite. Bioessays. 2000;22:72-83. Abstract.

Delfini M, Hirsinger E, Pourquié O, Duprez D. Delta1-activated Notch inhibits muscle differentiation without affecting Myf5 and Pax3 expression in chick limb myogenesis. Development. 2000;127:5213-5224. Abstract.

Fraboulet S, Schmidt-Petri T, Dhouailly D, Pourquié O. Expression of DM-GRASP/BEN in the developing mouse spinal cord and various epithelia. Mech Dev. 2000;95:221-224. Abstract.

Hirsinger E, Jouve C, Dubrulle J, Pourquié O. Somite formation and patterning. Int Rev Cytology. 2000;198:1-65. Abstract.

Jouve C, Palmeirim I, Henrique D, Beckers J, Gossler A, Ish-Horowicz D, Pourquié O. Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development. 2000;127:1421-1429. Abstract.

Leimeister C, Dale K, Fischer A, Klamt B, Hrabe de Angelis M, Radtke F, McGrew MJ, Pourquié O, Gessler M. Oscillating expression of c-hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors. Dev Biol. 2000;227:91-103. Abstract.

Olivera-Martinez I, Coltey M, Dhouailly D, Pourquié O. Medio-lateral somitic origin of ribs and dermis determined by quail-chick chimeras. Development. 2000;127:4611-4617. Abstract.

Pourquié O. Segmentation of the paraxial mesoderm and vertebrate somitogenesis. Curr Top Dev Biol. 2000;47:81-105. Abstract.

Pourquié O. Skin development: delta laid bare. Curr Biol. 2000;10:R425-R428. Abstract.

Pourquié O. Vertebrate segmentation: is cycling the rule? Curr Opin Cell Biol. 2000;12:747-751. Abstract.

Fournier-Thibault C, Pourquié O, Rouaud T, Le Douarin NM. BEN/SC1/DM-GRASP expression during neuromuscular development: a cell adhesion molecule regulated by innervation. J Neurosci. 1999;19:1382-1392. Abstract.

Pourquié O. Notch around the clock. Curr Opin Genet Dev. 1999;9:559-565. Abstract.

Fougerousse F, Durand D, Suel L, Pourquié O, Delezoide A-L, Romero N, Abitbol M, Beckmann J. Expression of genes(CAPN3, SGCA, SGCB, and TTN) involved in progressive muscular dystrophies during early human development. Genomics. 1998;48:145-156. Abstract.

Jarriault S, Le Bail O, Hirsinger E, Pourquié O, Logeat F, Strong CF, Brou C, Seidah NG, Israël A. Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol Cell Biol. 1998;18:7423-7431. Abstract.

McGrew M, Dale K, Fraboulet S, Pourquié O. Lunatic Fringe is a target of the segmentation clock linked to somite segmentation in avian embryos. Curr Biol. 1998;8:979-982. Abstract.

McGrew M, Xavier-Nieto J, Pourquié O, Rosenthal N. Molecular genetics of skeletal muscle genetics. In: Harvey RP, Rosenthal N, eds.  Heart Development. New York: Academic Press; 1998.

McGrew M, Pourquié O. Somitogenesis : segmenting a vertebrate. Curr Opin Genet Dev. 1998;8:487-494. Abstract.

Palmeirim I, Dubrulle J, Henrique D, Ish-Horowicz D, Pourquié O. Uncoupling segment formation from somitogenesis in the chick presomitic mesoderm. Dev Genet. 1998;23:77-86. Abstract.

Pourquié O. Clocks regulating Developmental processes. Curr Opin Neurobiol. 1998;8:665-670. Abstract.

Viallet JP, Prin F, Olivier-Martinez I, Hirsinger E, Pourquié O, Douhailly D. Chick Delta-1 gene expression and the formation of the feather primordia. Mech Dev. 1998;72:159-168. Abstract.

Hirsinger E, Duprez D, Jouve C, Malapert M, Cooke J, Pourquié O. Noggin acts downstream of Wnt1 and Sonic Hedgehog to antagonize BMP4 in avian somite patterning. Development. 1997;124:4605-4614. Abstract.

Palmeirim I, Henrique D, Ish-Horowicz D, Pourquié O. Avian Hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell. 1997;91:639-648. Abstract.

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